DE69623325T2 - 4-HYDROXYCOUMARIN-3-CARBOXAMIDE FOR THE TREATMENT OF NON-INSULIN-DEPENDENT DIABETES MELLITUS - Google Patents

Abstract

The present invention provides some novel 4-hydroxycoumarin-3-carboxamide derivatives and the use of a broad class of 4-hydroxycoumarin-3-carboxamide derivatives for the treatment of a patient suffering from or susceptible to diabetes mellitus.

Description

Field of the invention

The present invention relates to 4-hydroxycoumarin-3- carboxamides. In particular, the present invention relates to novel 4-hydroxycoumarin-3-carboxamides of the formulas IA, IB and IC and the use of 4-hydroxycoumarin-3-carboxamides of the formula I for the manufacture of a medicament for the treatment of non-insulin-dependent diabetes mellitus.

Background of the invention

Diabetes mellitus is a clinical syndrome characterized by inappropriate hyperglycemia caused by a lack of insulin or resistance to the action of insulin (insulin insensitivity). It is the most common endocrine disorder, affecting approximately 12 million people in the United States and perhaps as many as 200 million worldwide.

Resistance to the action of insulin is a common phenomenon and plays a central role in the pathogenesis and clinical course of several important human diseases. The fact that a large number of patients with diabetes are "insulin insensitive" was first demonstrated about 60 years ago. It was proposed that patients with diabetes should be divided into two categories, insulin sensitive and insulin insensitive. This view was institutionalized when the National Diabetes Data Group reached the same conclusion about 40 years after the original observations, and we now use the terms insulin dependent Diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM).

IDDM, commonly referred to as type I diabetes, is a disease of impaired immune function that involves the destruction of pancreatic β-cells that produce insulin. The onset of clinical symptoms of type I diabetes represents the end point of a chronic progressive decline in β-cell function and occurs when the majority of β-cells are lost, leading to absolute dependence on exogenous insulin.

Type II diabetes or NIDDM is a very different disease compared to IDDM. NIDDM classically develops in an older patient population and it may or may not require the use of therapeutic insulin. NIDDM is characterized by glucose intolerance and an impaired tissue sensitivity to the action of insulin, i.e., resistance to insulin-mediated glucose uptake by muscle. A two-stage model for the development of NIDDM has been proposed. M. F. Saad et al., Am. J. Chem. Vol. 90, pp. 229-35 (1991). The first stage is the development of impaired glucose tolerance, which depends on and is primarily determined by the emergence of insulin resistance. The second stage is the transition from impaired glucose tolerance to NIDDM, which is accompanied by further worsening of insulin resistance, with primary or secondary β-dysfunction playing a crucial role during the deterioration from impaired glucose tolerance to NIDDM.

In type I diabetes, the primary change is in the pancreas, leading to insulin deficiency, while in type 11 diabetes the underlying resistance of the tissues is to insulin can last for many years before a diagnosis of diabetes is made. Therefore, although the characteristics of type I and type II diabetes are very different, both can be treated with an agent that can either act similarly to insulin or can increase the activity of insulin.

International Publication No. WO 92/06083 discloses 3-carbamoyl-4-hydroxy-coumarin derivatives which are useful as antiparasitic agents, for example antihelminthics and anticoccidial agents.

International Publication No. WO 92/04327 discloses heterocyclic compounds useful as antihypertensive agents and as antiviral agents against DNA-containing viruses such as viruses of the herpes group.

International Publication No. WO 94/05649 discloses 3-phenylcarbamoyl-4-hydroxy-coumarin derivatives which are useful as broad-spectrum antibiotics, particularly active against gram-positive bacteria.

European patent publication 241834 discloses 3- aryl-carbamoyl-4-hydroxy-coumarin derivatives which are suitable as antihelminthics.

Derwent Abstracts 16517X/09 discloses an anti-helminthic agent with substituted benzopyran-3-carboxyanilides.

U.S. Patent No. 3,122,557 discloses coumarin-α-pyrone-3-carboxyamides which are useful as fungicides and bactericides.

Ho et al., J. Pharmaceutical Science 83(7), 1054 (1994), discloses certain antihelminthics. Lee et al., J. Labelled Compounds and Radiopharmaceuticals 33(9): 823-6 (1993), reports the synthesis of a labeled coumarin. These two references disclose the compound of formula IA (see below) where R10 is Cl, R11 and R12 are each H and R13 is bromophenyl.

Japanese Patent 4667 (February 25, 1967) discloses N-substituted 3-carbamoyl-4-hydroxycoumarins useful as antibacterial agents.

Summary of the invention

The present invention relates to the use of a compound of formula I or of pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of a patient suffering from or susceptible to non-insulin-dependent diabetes mellitus,

where:

R₁ (a) H,

(b) F,

(c) Cl or

(d) CH3;

R₂ (a) H,

(b) F,

(c) C1,

(d) Br or

(e) phenyl;

or R₁ and R₂ together form phenyl;

R₃ (a) H,

(b) C1,

(c) F,

(d) -NO₂,

(e) Phenoxy,

(f) Br or

(g) CF3;

R&sub4; (a) 3-carbamoyl-5-methylthien-2-yl,

(b) 5-(trifluoromethyl)-1,3,4-triazole,

R₅ (a) H or

(b) C1;

R6 (a) H,

(b) Br,

(c) F,

(d) Benzoyl,

(e) 5-trifluoromethyl-1,3,4-thiadiazol-2-oxy or

(f) (CH3 )CH-P-O(OEt2 );

R&sub7; (a) -SO2 CH3 ,

(b) -SO₂NH₂,

(c) -SO2 N(CH3 )2 ,

(d) CF3,

(e) CF₂Cl,

(f) CF₂H,

(g) Br,

(h) Cl or

(i) CF;

R�8 (a) H or

(b) Cl; and

R�9 (a) Br or

(b) CF3;.

The invention also includes compounds of formulas IA, IB, IC or pharmaceutically acceptable salts thereof:

where:

R₁₀ a) H or

b) C1;

R₁₁ a) H,

b) phenyl,

c) Cl/

d) F or

e) Br;

R₁₂ a) H,

b) CH3,

c) Cl or

d) F;

or R₁₁ and R₁₂ together form phenyl;

R&sub1;&sub3; a) 5-bromopyridin-2-yl,

b) 5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl,

c) 4-bromophenyl,

d) 5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl,

e) 5-(Pentafluoroethyl)-1,3,4-thiadiazol-2-yl or

f) 5-(Difluorochloromethyl)-1,3,4-thiadiazol-2-yl;

and where:

a) when R₁₀ is H, at least one of the radicals R₁₁ or R₁₂ is other than H,

b) when R₁₀ is Cl, R₁₁ is H and R₁₂ is H, then R₁₃ is not 4-bromophenyl.

R₁₄ a) H,

b) Cl or

c) NO2;

R&sub1;&sub5; a) 3-carbamoyl-5-methylthien-2-yl,

b) 4-bromophenyl,

c) 5-(trifluoromethyl)-1,3,4-triazol-2-yl,

d) 4-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yloxy]phenyl or

e) 4-benzoylphenyl;

and where:

a) when R₁₄ is H, R₁₅ is 3-carbamoyl-6-methylthien-2-yl or 4-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yloxy]phenyl,

b) when R₁₄ is Cl, R₁₅ is 4-benzoylphenyl or 5- (trifluoromethyl)-1,3,4-triazol-2-yl or

c) when R₁₄ is -NO₂, R₁₅ is 4-bromophenyl;

R₁₆ a) F,

b) C1,

c) Br,

d) CF₃ or

e) phenoxy;

R₁₇ a) CFaH,

b) CF3,

c) SO₂CH₃,

d) SO₂NH₂ or

e) SO₂(NH₃)₂;

and where

a) when R₁₇ is SO₂CH₃, SO₂NH₂ or SO₂N(CH₃)₂, R₁₆ is Cl ,

b) when R₁₇ is CF₃, R₁₆ is phenoxy, or

c) when R₁₇ is CF₂H, R₁₆ is F, Cl, Br or CF₃.

The compounds of formulas I, IA, IB and IC of the present invention have been found to be agents with the ability to enhance autophosphorylation of the insulin receptor, a necessary first step in the activity of insulin. The compounds improve the sensitivity of peripheral tissues to the action of insulin, i.e., insulin-mediated glucose uptake by muscle, and are therefore useful in the treatment of NIDDM. The compounds of formula I also exhibit effects on the incorporation of glucose into isolated cells in the absence of insulin.

Detailed description of the invention

The present invention provides some novel 4-hydroxycoumarin-3-carboxamide derivatives and the use of a broad class of 4-hydroxycoumarin-3-carboxamide derivatives for the treatment of non-insulin dependent diabetes mellitus (NIDDM).

NIDDM is characterized by glucose intolerance and impaired tissue sensitivity to the action of insulin. Insulin action is exerted through a specific cellular receptor for the hormone. The insulin receptor directs insulin to a specific target tissue and programs tissue responsiveness to insulin. The transmission of the insulin receptor signal involves a phosphorylation cascade, i.e. insulin induces autophosphorylation of the receptor, which activates the receptor kinase, which in turn phosphorylates one or more cellular substrates. These substrates may be enzymes (serine kinases or phosphoprotein phosphatases) or enzyme inhibitors whose activity is altered by these phosphorylation and dephosphorylation reactions. In most cases, reduced cellular sensitivity to insulin is not due to mutations in the receptor itself, but rather results from a weakening of the insulin signaling pathway, with the defect occurring at the level of the receptor. Therefore, compounds that can increase autophosphorylation of the receptor increase insulin signaling. Compounds of formula I according to the invention were identified by ELISA technique with the ability to enhance autophosphorylation of the insulin receptor, a necessary first step in the insulin signaling cascade. Compounds identified by this test also showed increased glucose uptake in the presence and absence of essence of insulin in vitro. Compounds of formula I were also administered to KKAy mice, rodent models of type II diabetes, and demonstrated reduction in glucose concentration, indicating improved glucose tolerance. Therefore, the compounds are suitable for the treatment of NIDDM.

Table 1 contains a list of compounds claimed for use in the treatment of diabetes mellitus and provides a summary of the increase in insulin receptor autophosphorylation induced by the corresponding compounds of the invention. The results in Table 1 are given as percentages of insulin receptor phosphotyrosine content in compound-treated cell lysates relative to untreated controls, both incubated in the presence of 2 nmol insulin. For example, cells incubated with compound No. 4 and 2 nmol insulin induced an increase in the phosphotyrosine content of the insulin receptor to a concentration 3.27 times higher than cells incubated with 2 nmol insulin alone (327%). In this test, a value of 150% is the minimum required for a compound to be considered active in increasing the insulin receptor response to insulin. The results in Table 1 are summarized under the heading "% of response to 2 nmol insulin."

Figure 1 illustrates the effect of 7-chloro-4-hydroxy-3-[N-[5- bromo-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin (compound no. 4) on isolated adipocytes. The data demonstrate that the compound increases glucose uptake in the presence and absence of insulin.

Figure 2 illustrates the effect of 7-chloro-4-hydroxy-3-[N-[5-bromo-1,3,4-thiadiazol-2-yl]carbamoyl]coumarin (Compound No. 4) in KKAy mice. Administration of the compound of the invention to KKAy mice at a dose of about 0.1-200 mg/kg body weight per day for three days reduced blood glucose levels in this rodent model of non-insulin dependent diabetes mellitus. A dose of 40 mg/kg body weight/day resulted in a 45% reduction in blood glucose levels. Higher doses resulted in greater reductions in blood glucose concentration. However, administration of compounds at more than 100 mg/kg/day resulted in a similar reduction in blood glucose concentration as achieved with 70 mg/kg/day. Therefore, the dose to be used for compounds of formula I is between 0.1 and 100 mg/kg/body weight per day. The preferred dose is 0.1-50 mg/kg/day. KKAy mice are insulin resistant and the observation that blood glucose levels are reduced in these animals without fasting indicates that insulin resistance is very likely to be reduced following treatment with the claimed compounds.

A patient suffering from or susceptible to diabetes mellitus means a person with inappropriate hyperglycemia caused by insulin deficiency or resistance to the action of insulin (insulin insensitivity). Treatment means reducing or partially or completely eliminating inappropriate hyperglycemia in a patient. The diagnosis for these patients is readily made by a physician of ordinary skill.

The compounds of formulas I, IA, IB and IC according to the invention can be prepared by the processes described in International Publication No. WO 92/06083, International Publication No. WO 94/05649, Japanese Patent 4668, U.S. Patent 3,122,557, U.S. Patent 3,726,892, Swiss Patent 513585, and J. Chem. Soc. p. 1508 (1958). Reaction Scheme I illustrates a general procedure for the preparation of compounds of formula IA, IB, and IC. Example 1 provides a detailed description for the preparation of compounds of formula IA, IB, and IC.

The compounds of formula I can also be in the form of a pharmaceutically acceptable salt for the treatment of diabetes mellitus. The term "pharmaceutically acceptable salt" refers to salts suitable for administering the compounds of the invention and these include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. These salts may be in hydrate form. Some of the compounds of the invention may form metal salts such as sodium, potassium, calcium and magnesium salts and these are encompassed by the term "pharmaceutically acceptable salts".

The compounds of the invention can be administered to humans in any number of conventional dosage forms, for example, orally, rectally, parenterally, topically, transdermally, by inhalation, and the like. Oral or rectal dosage forms include capsules, tablets, pills, powders, cachets, and suppositories. Liquid oral dosage Administration forms include solutions and suspensions. Parenteral preparations include sterile solutions and suspensions. Administration by inhalation may be in the form of a nasal or oral spray or by sniffing. Topical dosage forms may be creams, ointments, lotions, transdermal devices (e.g., of the conventional patch or matrix type), and the like. In general, the preferred form of administration is oral.

The formulations and pharmaceutical compositions contemplated in the above dosage forms may be prepared with conventional pharmaceutically acceptable excipients and additives using conventional techniques. These pharmaceutically acceptable excipients and additives are intended to include carriers, binders, flavorings, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersing agents, suspending agents, fragrances, preservatives, lubricants, and the like.

Biological tests

The compounds of the invention were tested for their ability to increase autophosphorylation of the insulin receptor, to improve glucose incorporation in vitro in the presence and absence of insulin, and to reduce blood glucose in vivo. The present invention will be more clearly understood by the methods set out below.

Procedure 1 Increase in autophosphorylation of the insulin receptor

Insulin signaling is mediated by a phosphorylation cascade that occurs at the receptor following an interaction cation initiated with insulin; therefore, compounds capable of increasing autophosphorylation of the receptor increase insulin signaling. To demonstrate the increase in insulin receptor autophosphorylation induced by the compounds of the invention, an assay was developed to monitor the tyrosyl phosphorylation state of the insulin receptor. A CHO cell line stably transfected with an expression plasmid encoding the human insulin receptor is seeded into 96-well plates. After exposure to 2 nmol doses of insulin and 100 µmol of the test compounds, a postnuclear lysate is prepared by detergent lysis. The lysates are dispensed into 96-well plates coated with the plant lectin Lens Culinaris agglutinin, which binds to the insulin receptor. After washing, the phosphorylation state of the insulin receptor is monitored using a mouse antiphosphotyrosine antibody coupled to a goat antimouse antibody conjugated to horseradish peroxidase. The quantitative outcome of the reaction is determined by reading the absorbance at 450 nm. Table 1 contains a list of compounds claimed for use in the treatment of diabetes mellitus and provides a summary of the increase in insulin receptor autophosphorylation induced by the corresponding compounds of the invention. These compounds all significantly increased the ability of insulin to stimulate the phosphotyrosine content of the insulin receptor detected in the lysates of cells incubated in the co-presence of the compound and a submaximal dose of insulin (2 mmol). The results in Table 1 are expressed as percentages of the phosphotyrosine content of the insulin receptor in cell lysates treated with a compound relative to untreated Controls, both incubated in the presence of 2 mmol insulin, are given.

Procedure 2 Improvement of glucose incorporation in isolated adipocytes

To demonstrate the enhancement of glucose uptake in vitro, rat adipocytes were isolated from the epididymal fat pad and incubated with a concentration of 0-100 µmol of 7-chloro-4-hydroxy-3-[N-[5-bromo-1,3,4-thiadiazol-2-yl]carbamoyl]coumarin (Compound No. 4) for 15 min before 0.1 nmol was added for 5 min. Over a period of 30 min, the incorporation of 6-3-H-glucose was determined according to the procedure described in McCroskey et al., Biochem. Biophys. Acta, Vol. 1011, pp. 212-219 (1989). In addition, a parallel test was performed without insulin exposure (basal). As shown in Fig. 1, the compound increases glucose uptake in the presence and absence of insulin.

Procedure 3 Reduction of blood glucose in KKAy mice

To test the effect of compounds of formula I on blood glucose in KKAy mice, mice were given 7-chloro-4-hydroxy-3-[N-[5-bromo-1,3,4-thiadiazol-2-yl]carbamoyl]coumarin (Compound No. 4) in rodent diet. KKAy mice are rodent models of NIDDM. A pretreatment blood sample was obtained from the retro-orbital sinus and mice were arranged in groups of six such that the mean pretreatment blood glucose level was the same on average in all groups. Test compounds were mixed into the diet to achieve daily doses of 50-200 mg. Mice were allowed to eat the diet ad libitum.

Control mice received unsupplemented food. On day 0, mice received control food or food supplemented with test compounds. After 3 days of consuming control food or food supplemented with test compounds, a blood sample was collected and plasma analyzed to determine glucose concentration. Food intake was determined by weighing the food provided at the beginning of the study and the food leftover at the end of the study. Food intake was calculated by subtracting the weight of the leftover from the weight of the food provided. Drug intake was calculated from the compound content of the food and the total food intake. Administration of the compound of the invention to KKAy mice at a dose of about 0.1-200 mg/kg body weight per day for 3 days reduced blood glucose levels in these rodent models of non-insulin dependent diabetes mellitus. A dose of 40 mg/kg body weight/day resulted in a 45% decrease in blood glucose levels. Higher doses resulted in greater reductions in blood glucose concentration. However, administration of compounds greater than 100 mg/kg/day resulted in approximately similar changes in blood glucose concentration to that achieved with 70 mg/kg/day. Therefore, using this procedure, a significant reduction in blood glucose occurred in KKAy mice at doses of 10-50 mg/kg/day. Experience suggests that doses may be 5-10-fold lower in humans compared to mice. Blood glucose data are reported as the average blood glucose concentration in the test group. Results are summarized in Fig. 2.

example 1 Preparation of 6-chloro-4-hydroxy-3[N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]coumarin step 1 Preparation of 6-chloro-4-hydroxy-2-oxo-2H-1- benzopyran-3-carboxylic acid ethyl ester

To a suspension of magnesium ethoxide (4.56 g, 39.8 mmol) in toluene (30 mL) in a flame-dried flask under nitrogen is added diethyl malonate (6.5 mL, 43.2 mmol). The resulting suspension is stirred at ambient temperature for 3 h and then cooled to 0 °C. In a separate flask, a suspension of 6-fluorosalicylic acid (5.19 g/33.2 mmol) in toluene (100 mL) is cooled to 0 °C. Triethylamine (9.3 mL, 66.5 mmol) is added to give a clear solution. Ethyl chloroformate (6.7 mL, 69.7 mmol) is added slowly so that the reaction temperature cannot rise above 10 °C. After stirring for an additional hour at 0°C, the diethyl malonate solution is added in several portions such that the reaction temperature does not rise above 10°C. The reaction mixture is stirred for an additional hour at 0°C and then allowed to reach ambient temperature and stirred overnight. The reaction mixture is diluted with 100 mL of toluene, quenched with HCl (3 M aqueous) and stirred for 30 min. The organic phase is separated and washed with 3 M aqueous HCl, H₂O, saturated aqueous NaHCO₃ solution and H₂O. The organic phase is concentrated to a yellow oil which is dissolved in aqueous NaOH (3 M) and allowed to stand. The resulting precipitate is collected, acidified with aqueous citric acid (1 M) and dissolved in CH₂Cl₂. (4 x 125 mL). Drying over MgSO4, filtering and concentrating in vacuo gave a crude beige solid which was recrystallized from ethyl acetate to give the title compound as a white solid.

1 NMR (CDCl3 ): d 1.45, 4.50, 7.24, 7.59, 7.95, 14.73.

Level 2 Preparation of 6-chloro-4-hydroxy-3-[N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]coumarin

To a suspension of ethyl 6-chloro-4-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate (1.01 g, 3.76 mmol) in xylene (10 mL) is added 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (636 mg, 3.76 mmol). The resulting suspension is heated to reflux and stirred overnight at this temperature. After cooling to room temperature, the resulting precipitate is collected, washed well with methanol and dried to give the title compound as a solid.

1 H-NMR (DMSO-d6 ): d 7.23, 7.59, 7.87, 11.79, 14.98.

Following the general procedure of Example 1, the new coumarinamides indicated below are prepared.

4-Hydroxy-6-phenyl-3-[N-(5-bromopyridin-2-yl)carbamoyl]-coumarin mp 273.5°C;

3-[N-(3-carbamoyl-5-methylthien-2-yl)carbamoyl]-4-hydroxycoumarin mp 283-285°C;

6-Fluoro-4-hydroxy-3-[N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin mp 264.8°C;

4-Hydroxy-7-nitro-3-[N-(4-bromophenyl)carbamoyl]-coumarin mp 277°C;

4-Hydroxy-5-methyl-3-[N-(4-bromophenyl)carbamoyl]-coumarin mp 197.3°C;

5-Chloro-4-hydroxy-3-[N-(4-bromophenyl)carbamoyl]-coumarin mp 236.2°C;

5-Chloro-4-hydroxy-3-[N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin mp 260.7°C;

7-Chloro-4-hydroxy-3-[N-[5-(trifluoromethyl)-1,3,4-triazol-2-yl]carbamoyl]-coumarin mp 261.2°C;

4-Hydroxy-3-[N-(4-(5-trifluoromethyl)-1,3,4-thiadiazol-2-yloxy)phenyl)carbamoyl]-coumarin mp 236.5°C;

7-Chloro-4-hydroxy-3-[N-(4-benzoylphenyl)carbamoyl]-coumarin mp 242-246°C;

7-Bromo-4-hydroxy-3-[N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin mp 254.5°C;

6,7-Dichloro-4-hydroxy-3-[N-(4-bromophenyl)carbamoyl]-coumarin mp 256-258°C;

7-Trifluoromethyl-4-hydroxy-3-[N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin mp 268-270°C;

1-Hydroxy-2-[N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-3H-naphtho[2,1-b]pyran-3-one m.p. 264-265°C ;

5-Fluoro-4-hydroxy-3-[N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin mp 264-265°C;

5-Fluoro-4-hydroxy-3-[N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin mp 224-225°C;

6-Fluoro-4-hydroxy-3-[N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin mp 224-225°C;

5-Fluoro-4-hydroxy-3-[N-[5-(pentafluoroethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin mp 240-242°C;

5-Fluoro-4-hydroxy-3-[N-[5-(difluorochloromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin mp 243-244°C;

6-Bromo-4-hydroxy-3-[N-[5-(difluorochloromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin mp 227-228°C;

6-Chloro-4-hydroxy-3-[N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin mp 238-240°C;

7-Chloro-4-hydroxy-3-[N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin

¹NMR (DMSO-dg): d7/29, 7.37, 7.44, 7.91, 10.68, 14.31;

7-Fluoro-4-hydroxy-3-[N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin

¹H-NMR (DMSO): § 7.08-7.16, 7.43, 8.00, 14.74;

7-Chloro-4-hydroxy-3-[N-[5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin mp 293-294°C;

7-Chloro-4-hydroxy-3-[N-[5-(aminosulfonyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin mp 267-269°C;

4-Hydroxy-7-phenoxy-3-[N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin mp 250-253°C;

7-Chloro-4-hydroxy-3-[N-[5-(dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin Mp 273-276 Reaction Scheme I Table 1 Increase in insulin receptor autophosphorylation

Claims (9)

1. Use of a compound of formula I or of pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating a patient suffering from or susceptible to non-insulin-dependent diabetes mellitus, where: R₁ (a) H, (b) F, (c) Cl or (d) CH3; R₅ (a) H, (b) F, (c) C1, (d) Br or (e) phenyl; or R₁ and R₂ together form phenyl; R₃ (a) H, (b) C1, (c) F, (d) -NO₂, (e) Phenoxy, (f) Br or (g) CF3; R&sub4; (a) 3-carbamoyl-5-methylthien-2-yl, (b) 5-(trifluoromethyl)-1,3,4-triazole, R₅ (a) H or (b) C1; R6 (a) H, (b) Br, (c) F, (d) Benzoyl, (e) 5-trifluoromethyl-1,3,4-thiadiazol-2-oxy or (f) (CH3 )CH-P-O(OEt2 ); R&sub7; (a) -SO2 CH3 , (b) -SO₂NH₂, (c) -SO2 N(CH3 )2 , (d) CF3, (e) CF₃Cl, (f) CF₂H, (g) Br, (h) Cl or (i) CF₂CF₃; R�8 (a) H or (b) Cl; and R�9 (a) Br or (b) CF3;. 2. Use according to claim 1, wherein the compound of formula I is administered orally, parenterally or topically in a pharmaceutical composition. 3. Use according to claim 1, wherein the compound of formula I is administered orally in a pharmaceutical composition. 4. Use according to claim 1, wherein the effective amount of the compound of formula I is in the range of 0.1-100 mg/kg body weight/day. 5. Use according to claim 1, wherein the effective amount of the compound of formula I is in the range of 0.1-50 mg/kg body weight/day. 6. Use according to claim 1, wherein the compound of formula I is: (a) 4-Hydroxy-6-phenyl-3-[N-(5-bromopyridin-2-yl)carbamoyl]-coumarin; (b) 7-chloro-4-hydroxy-3-[N-[5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (c) 7-chloro-4-hydroxy-3-[N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (d) 3-[N-(3-carbamoyl-5-methylthien-2-yl)carbamoyl]-4-hydroxycoumarin; (e) 6-fluoro-4-hydroxy-3-[N-[5-(trifluoromethyl)-1,3,4-fchiadiazol-2-yl]carbamoyl]-coumarin; (f) 4-Hydroxy-7-nitro-3-[N-(4-bromophenyl)carbamoyl]-coumarin; (g) 4-Hydroxy-5-methyl-3-[N-(4-bromophenyl)carbamoyl]-coumarin; (h) 5-chloro-4-hydroxy-3-[N-(4-bromophenyl)carbamoyl]-coumarin; (i) 5-chloro-4-hydroxy-3-[N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (j) 7-fluoro-4-hydroxy-3-[N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (k) 4-Hydroxy-3-[N-(4-fluorophenyl)carbamoyl]-coumarin; (l) 7-Chloro-4-hydroxy-3-[N-[5-(chlorodifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (m) 7-chloro-4-hydroxy-3-[N-[5-bromo-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (n) 4-Hydroxy-3-[N-[5-chloro-1,3,4-thiadiazol-2-yl]carbamomyl]-coumarin; (o) 7-Chloro-4-hydroxy-3-[N-[5-chloro-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (p) 7-Chloro-4-hydroxy-3-[N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (q) 4-Hydroxy-3-[N-(3-chloro-5-(trifluoromethyl)-pyridin-2-yl)carbamoyl]-coumarin; (r) 7-Chloro-4-hydroxy-3-[N-[5-(trifluoromethyl)-1,3,4-triazol-2-yl]carbamoyl]-coumarin; (s) 7-chloro-4-hydroxy-3-[N-[4-(1-diethylphosphonyl)ethyl)-phenyl]carbamoyl]-coumarin; (t) 4-Hydroxy-3-[N-(4-(5-trifluoromethyl)-1,3,4-thiadiazol-2-yloxy)phenyl)carbamoyl]-coumarin; (u) 7-chloro-4-hydroxy-3-[N-(4-benzoylphenyl)carbamoyl]coumarin; (v) 4-Hydroxy-7-phenoxy-3-[N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (w) 7-chloro-4-hydroxy-3-[N-(2-chlorophenyl)carbamoyl]-coumarin; (x) 6,7-Dichloro-4-hydroxy-3-[N-(4-bromophenyl)carbamoyl]-coumarin; (y) 4-Hydroxy-7-trifluoromethyl-3-[N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (z) 4-Hydroxy-7-trifluoromethyl-3-[N-[5-(pentafluoroethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (aa) 7-Bromo-4-hydroxy-3-[N-[5-(chlorodifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (bb) 7-bromo-4-hydroxy-3-[N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (cc) 6-Chloro-4-hydroxy-3-[N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (dd) 7-trifluoromethyl-4-hydroxy-3-[N-[5-(difluorochloromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (ee) 7-fluoro-4-hydroxy-3-[N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (ff) 7-Trifluoromethyl-4-hydroxy-3-[N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (gg) 7-fluoro-4-hydroxy-3-[N-[5-(difluorochloromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (hh) 7-chloro-4-hydroxy-3-[N-[5-(aminosulfonyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (ii) 7-chloro-4-hydroxy-3-[N-[5-(dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (jj) 1-Hydroxy-2-[N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-3H-naphtho[2,l-b]pyran-3-one; (kk) 5-fluoro-4-hydroxy-3-[N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (II) 5-fluoro-4-hydroxy-3-[N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (mm) 6-Fluoro-4-hydroxy-3-[N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (nn) 5-fluoro-4-hydroxy-3-[N-[5-(pentafluoroethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (oo) 5-fluoro-4-hydroxy-3-[N-[5-(difluorochloromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin; (pp) 6-Bromo-4-hydroxy-3-[N-[5-(difluorochloromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin or (qq) 6-Chloro-4-hydroxy-3-[N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-coumarin. 7. Compound of formula IA or pharmaceutically acceptable salts thereof, wherein : R₁₀ a) H or b) C1; R₁₁ a) H, b) phenyl, c) C1, d) F or e) Br; R₁₂ a) H, b) CH3, c) Cl or d) F; or R₁₁ and R₁₂ together form phenyl; R&sub1;&sub3; a) 5-bromopyridin-2-yl, b) 5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl, c) 4-bromophenyl, d) 5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl, e) 5-(Pentafluoroethyl)-1,3,4-thiadiazol-2-yl or f) 5-(difluorochloromethyl)-1,3,4-thiadiazol-2-yl; and where: a) when R₁₀ is H, at least one of R₁₁ is or R₁₂ is different from H, b) when R₁₀ is Cl, R₁₁ is H and R₁₂ is H, then R₁₃ is not 4-bromophenyl. 8. Compound of formula IB or pharmaceutically acceptable salts thereof, wherein : R₁₄ a) H, b) Cl or c) NO2; R&sub1;&sub5; a) 3-carbamoyl-5-methylthien-2-yl, b) 4-bromophenyl, c) 5-(trifluoromethyl)-1,3,4-triazol-2-yl, d) 4-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yloxy]phenyl or e) 4-benzoylphenyl; and where: a) when R₁₄ is H, R₁₅ is 3-carbamoyl-5-methylthien-2-yl or 4-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yloxy]phenyl, b) when R₁₄ is Cl, R₁₅ is 4-benzoylphenyl or 5- (trifluoromethyl)-1,3,4-triazol-2-yl or c) when R₁₄ is -NC, R₁₅ is 4-bromophenyl. 9. Compound of formula IC or pharmaceutically acceptable salts thereof, wherein : R₁₆ a) F, b) C1, c) Br, d) CF₃ or e) phenoxy; R₁₇ a) CF₂H, b) CF3, c) SO₂CH₃, d) SO₂NH₂ or e) SO₂N(CH₃)₂; and where a) when R₁₇ is SO₂CH₃, SO₂NH₂ or SO₂N(CH₃)₂, R₁₆ is Cl , b) when R₁₇ is CF₃, R₁₆ is phenoxy, or c) when R₁₇ is CF-H, R₁₆ is F, Cl, Br or CF₃.